Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent®) a VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor in a phase II trial
Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this re...
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| Veröffentlicht in: | Journal of hematology and oncology 2014-08, Vol.7 (1), p.52-52, Article 52 |
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| creator | Subbiah, Vivek Meric-Bernstam, Funda Mills, Gordon B Shaw, Kenna R Mills Bailey, Ann Marie Rao, Priya Ward, John F Pagliaro, Lance C |
| description | Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States.
Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.
Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.
Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.
ClinicalTrials.gov Identifier: NCT00912912. |
| doi_str_mv | 10.1186/s13045-014-0052-x |
| format | Article |
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Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.
Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.
Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.
ClinicalTrials.gov Identifier: NCT00912912.</description><identifier>ISSN: 1756-8722</identifier><identifier>EISSN: 1756-8722</identifier><identifier>DOI: 10.1186/s13045-014-0052-x</identifier><identifier>PMID: 25085632</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Adolescent ; Adult ; Antineoplastic Agents - therapeutic use ; Disease-Free Survival ; Drug Resistance, Neoplasm - genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Indoles - therapeutic use ; Male ; Mediastinal Neoplasms - drug therapy ; Mediastinal Neoplasms - genetics ; Mediastinal Neoplasms - mortality ; Middle Aged ; Neoplasms, Germ Cell and Embryonal - drug therapy ; Neoplasms, Germ Cell and Embryonal - genetics ; Neoplasms, Germ Cell and Embryonal - mortality ; Platinum Compounds - therapeutic use ; Protein Kinase Inhibitors - therapeutic use ; Proto-Oncogene Proteins c-ret - genetics ; Pyrroles - therapeutic use ; Retroperitoneal Neoplasms - drug therapy ; Retroperitoneal Neoplasms - genetics ; Retroperitoneal Neoplasms - mortality ; Testicular Neoplasms - drug therapy ; Testicular Neoplasms - genetics ; Testicular Neoplasms - mortality ; Young Adult</subject><ispartof>Journal of hematology and oncology, 2014-08, Vol.7 (1), p.52-52, Article 52</ispartof><rights>Copyright © 2014 Subbiah et al.; licensee BioMed Central Ltd. 2014 Subbiah et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c399t-aa63cb3310ffc54fd02d4640f63dc24a8a3ab9b48fa56a333b5f703a5fd6a3533</citedby><cites>FETCH-LOGICAL-c399t-aa63cb3310ffc54fd02d4640f63dc24a8a3ab9b48fa56a333b5f703a5fd6a3533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237879/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237879/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25085632$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Subbiah, Vivek</creatorcontrib><creatorcontrib>Meric-Bernstam, Funda</creatorcontrib><creatorcontrib>Mills, Gordon B</creatorcontrib><creatorcontrib>Shaw, Kenna R Mills</creatorcontrib><creatorcontrib>Bailey, Ann Marie</creatorcontrib><creatorcontrib>Rao, Priya</creatorcontrib><creatorcontrib>Ward, John F</creatorcontrib><creatorcontrib>Pagliaro, Lance C</creatorcontrib><title>Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent®) a VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor in a phase II trial</title><title>Journal of hematology and oncology</title><addtitle>J Hematol Oncol</addtitle><description>Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States.
Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.
Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.
Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.
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However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States.
Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.
Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.
Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.
ClinicalTrials.gov Identifier: NCT00912912.</abstract><cop>England</cop><pub>BioMed Central</pub><pmid>25085632</pmid><doi>10.1186/s13045-014-0052-x</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Adult Antineoplastic Agents - therapeutic use Disease-Free Survival Drug Resistance, Neoplasm - genetics High-Throughput Nucleotide Sequencing Humans Indoles - therapeutic use Male Mediastinal Neoplasms - drug therapy Mediastinal Neoplasms - genetics Mediastinal Neoplasms - mortality Middle Aged Neoplasms, Germ Cell and Embryonal - drug therapy Neoplasms, Germ Cell and Embryonal - genetics Neoplasms, Germ Cell and Embryonal - mortality Platinum Compounds - therapeutic use Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins c-ret - genetics Pyrroles - therapeutic use Retroperitoneal Neoplasms - drug therapy Retroperitoneal Neoplasms - genetics Retroperitoneal Neoplasms - mortality Testicular Neoplasms - drug therapy Testicular Neoplasms - genetics Testicular Neoplasms - mortality Young Adult |
| title | Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent®) a VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor in a phase II trial |
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